Grafting genetically-modified Schwann cells into a clinically-relevant model of SCI Spinal cord injury (SCI) is devastating, causing sensorimotor deficiencies, and possibly, complete paralysis. Unfortunately, there is no effective treatment, with hundreds of thousands living with the disorder and thousands more diagnosed each year. Overcoming primary damage, in addition to secondary tissue injury and glial scar formation, is critical for promoting axonal regeneration and functional recovery following SCI. Cell transplantation is a promising potential treatment for SCI. Schwann cells (SCs) are the most widely studied and these cells exhibit many benefits following SCI, such as promoting axonal regeneration and enhancing myelination. Though these functions are certainly advancements in SCI treatment, the full potential of SC transplantation has yet to be uncovered. Contusive injuries are one of the most commonly diagnosed forms of SCI, however much research has utilized hemi- or transection models, which are of less clinical value. Using SCs genetically modified to overexpress neurotrophic factors is promising as a potential treatment following SCI. We have recently shown that transplanting SCs engineered to overexpress glial cell line-derived neurotrophic factor (SC-GDNF) enhances neuroprotection and repair following SCI, and promotes astrocytic migration into the graft site, reducing inhibitory glial scar components in a hemisection SCI model. Also, co- administering SCs with GDNF following contusive SCI promotes significant neuroprotection and regeneration compared to SC transplantation alone. However, it is still not known what the short and long-term benefits of SC-GDNF transplantation are in contusive spinal cord injury. Also, the mechanism by which GDNF mediates structural protection and repair, or, very importantly, recovery of function, remains unknown. Activating mTOR, a pro-survival protein in the PI3K-Akt pathway may be one potential way GDNF exerts such effects. In addition, the long-term effects of GDNF expression by transplanted SCs on host tissue and function is unclear. To fully optimize this therapy for potential clinical use, it is essential to characterize the GDNF effect on neuroprotection, functional recovery and axonal regeneration in sub-chronic and chronic stages following contusive SCI, as well as its mechanism in enhancing neural regrowth following injury . In line with these goals, we hypothesize that transplanting SC engineered to overexpress GDNF into a thoracic contusive spinal cord lesion will 1) enhance neuroprotection, axonal sparing/regeneration, and functional recovery within a sub- chronic time course 2) promote and enhance such benefits into long-term chronic stages following SCI 3) enhance neurite outgrowth via activation of mTOR as a novel mechanism of its action. PUBLIC HEALTH RELEVANCE: Spinal cord injury affects over 200,000 individuals, with over 10,000 new cases per year. There is currently no effective treatment, though cell transplantation is a promising option. This study plans to investigate the effects of transplanting genetically-modified cells, Schwann cells, for repairing and protecting injured tissue and improving function following spinal cord injury.